Introduction on Vestibular Disorders
Vestibular (inner ear) disorders can cause dizziness, vertigo, imbalance, hearing changes, nausea, fatigue, anxiety, difficulty concentrating, and other symptoms, with potentially devastating effects on a person's day-to-day functioning, ability to work, relationships with family and friends, and quality of life.
For example, vestibular neuritis is the primary cause of hospitalisation for non neurological vertigos. Because its aetiology is largely unknown, epidemiological studies are variable depending on the source (the incidence is believed to be between 3.5 and 50 new cases for 100000 persons/per year). In the past, either an inflammation of the vestibular nerve, a reactivation of herpes simplex virus type 1 or labyrinthine ischemia was proposed as a cause of vestibular neuritis. Currently, a viral cause is favoured. A reactivation of herpes simplex virus type 1 would explain the repetition of the vertigo crisis under such circumstances. However, only the involvement of inflammatory pathophysiological mechanisms has been established.
Vestibular disorders may be also involved in the majority of the falls in the elderly population and their prevention has become a priority. The falls in the elderly population indeed represents more than 1% of the total budget of the health insurance in France (INSEE 1990), affecting 30% of people above 65 and 50% above 80. Falls in the elderly population are involved in ⅔ of deaths caused by accident above 65, increasing the risk of death by a factor of 4 in a given year.
Aetiology of Vestibular Disorders
Although the aetiology of vestibular disorders is mostly unknown, it is widely accepted that vestibular disorders constitute a vast family of conditions wherein the vestibular organ is associated. These disorders may be distinguished by their putative origins, one can thus identify (1) lesional vestibular disorders and (2) non lesional vestibular disorders.
1) Lesional vestibular disorders refer to vestibular disorders wherein lesions of inner ear cells and/or vestibular nerve are present or will appear during the disorder time course. In this case, the functionality of the vestibule is impaired as it can be observed using clinical functional tests (VOR, VNG). Lesional vestibular disorders include:                vestibular disorders wherein an inflammation of the inner ear and/or the vestibular nerve induces reversible and/or irreversible damages. One example of conditions from this group is vestibular neuritis;        vestibular disorders wherein inner ear fluids are affected (abnormalities in the quantity, composition, and/or pressure of the endolymph), these disorders usually develop lesions during the disease time course. Examples of conditions from this group are Menière's disease and secondary endolymphatic hydrops. They are currently associated with tinnitus and hearing loss;        vestibular disorders induced by insults or lesions of the vestibular endorgans. Examples of said conditions are vertigo caused by local ischemia, excitotoxicity, trauma that affect temporal bones or ototoxic insult to vestibular hair cells by drugs such as gentamicin and cisplatin.2) Non-lesional vestibular disorders refer to vestibular disorders supported by transient and often iterative vertigo crisis wherein no lesion on inner ear cells and/or vestibular nerve can be observed. In this case, the functionality of the vestibule evaluated between the vertigo crisis using functional tests (VOR, VNG) does not differ from healthy vestibule. Non-lesional vestibular disorders include:        vestibular disorders wherein debris had been collected within a part of the inner ear. This debris, called otoconia, is made up of small crystals of calcium carbonate and when they shift, they send false signals to the brain. Examples of said conditions are positional vertigos;        iterative vestibular disorders of unknown origin without tinnitus or hearing loss.Evaluation of the Vestibule Functional Loss        
In patients, morphofunctional alterations of the vestibular endorgans cannot be evaluated directly (except for large lesions that can be detected by MRI). Conversely, indirect assessment methods are currently used to evaluate the loss of functionality of the vestibule. These testing methods are generally conducted at ENT clinic/hospitals. Among them we can cite the vestibulonystagmography (VNG) and assessment of the vestibuloocculomotor reflex (VOR) using caloric or rotational tests, head impulse testing (HIT) and vestibular evoked myogenic potentials (VEMP).
Treatments of Vestibular Disorders
Current treatment of vestibular disorders mainly focus on reducing the vertigo crisis using vestibuloplegic drugs, while limiting neurovegetative reactions by using anti emetic drugs. Corticosteroids and antiviral drugs are the only medication used indirectly in an attempt to limit the spread of vestibular damages in the case of vestibular neuritis (if assumed to be due to bacterial or virus infections), by treating the putative cause of the vestibular dysfunction. Their effect remains under debate due to the lack of established aetiology in most vestibular deficits and have been suggested to only improve resolution of the initial peak crisis without improving long term patient outcome. For example, recovery after vestibular neuritis is usually incomplete. In a study of 60 patients, horizontal semicircular canal paresis was found in about 90% one month after the onset of symptoms, and in 80% after six months; the caloric responses eventually normalized in only 42%. On the basis of the incidence of this condition, a substantial and permanent unilateral dynamic deficit of the vestibulo ocular reflex, which cannot be completely compensated for by other mechanisms, develops in approximately 4000 person per year in the United States. This deficit leads to impaired vision and postural imbalance during walking and especially during head movement toward the affected ear.
Accordingly, there is a need for a protective or reparative therapy that prevents, reduces or treats the incidence and/or severity of lesional vestibular disorders, said functional alteration of the inner ear cells and/or vestibular nerve being due to inflammations, lesions or insults of diverse origins.
The inventors surprisingly found that calcineurin inhibitors were able to prevent or treat vestibular lesions by protecting inner ear cells and vestibular nerve from damage or degeneration.